The objectives of the proposed research are to provide information concerning factors regulating the secretion and biosynthesis of glucagon and their possible alteration in disorders of carbohydrate metabolism. The specific questions posed include: 1) Does the heterogeneous group of substances immunologically detected as glucagon (IRG) derived from the alpha cell represent a spectrum of precursors and degradation products of the glucagon of molecular weight of 3500 daltons? 2) Do the secretory products from extrapancreatic alpha cells contribute to the circulating pool of precursors of 3500 dalton glucagon in the primate? 3) Are there differences in the circulating IRG profiles and alpha cell responses to specific secretagogues between populations of humans with idiopathic diabetes mellitus characterized as a) juvenile-onset, insulin-dependent and b) maturity-onset, insulin-independent? 4) Is it possible to demonstrate glucagon-like biologic activity in any of the heterogeneous components measured as immunoreactive glucagon? 5) Does short or long term precise regulation of glucose concentrations in diabetic humans and baboons reverse the distorted alpha cell function observed in these disorders? 6) What are the factors governing the biosynthesis of glucagon in monolayer pancreatic islets from normal neonatal rats and human fetuses? 7) Can altered biosynthesis be demonstrated in insulin insufficiency induced pharmacologically? The proposed studies will be performed in 1) normal, diabetic and intestinally resected man and baboon, and 2) monolayer cultured rat and human islets. Perturbations of IRG levels will be made and sampled from regional circulations. Molecular species of IRG will be characterized by gel filtration and electrophoresis. Conditions for incorporation of labeled amino acids into glucagon precursors will be examined in cultured cells.